1. Field of the Invention
The present invention relates to the identification and control of gene targets for treatment of cancers, including chemoresistant and/or radioresistant cancers.
2. Description of the Background of the Invention
Cancer is not fully understood on a molecular level and remains a leading cause of death worldwide. One of the deadliest forms of cancer is solid tumors. One such solid tumor is lung cancer, the most common cancer worldwide and the leading cause of cancer-related death in the United States. Approximately 219,000 new diagnoses and over 159,000 deaths from lung cancer occur annually in the United States. Approximately 85% of lung cancers are non-small cell histology (NSCLC), including lung adenocarcinomas, which are the most common lung cancer type in the U.S. Treatment of early and intermediate stage NSCLC usually involves surgery, stereotactic radiotherapy, or conventional radiotherapy with or without adjuvant chemotherapy. Chemotherapy regimens for lung cancer, either concurrent with radiotherapy (RT) or adjuvant to surgery, usually incorporate platinum-based drugs such as cisplatin or carboplatin, as this has been shown to confer a survival advantage when either combined with radiotherapy or in the adjuvant setting.
Standard fractionated radiotherapy as the primary treatment for NSCLC is reserved for patients with tumors too advanced to resect, who are medically unstable, whose disease has spread beyond the chest, or in the case of small or metastatic tumor hypofractionated stereotacktic body radiotherapy. The utility of postoperative radiotherapy is controversial and subsets of patients who are likely to benefit have been proposed. These include patients with advanced lymph node metastases (N2-N3 or extra-capsular extension) and close or positive surgical margins. However, clear clinical and/or molecular selection criteria for patients who may benefit from postoperative radiotherapy remains elusive. No prognostic or predictive signature to select patients with NSCLC who may benefit from radiotherapy or chemotherapy is consistently used in clinical practice at this time.
The activity of Jak/Stat dependent genes has been shown to predict the outcome of patients with lung cancer and their response to the adjuvant radiotherapy or chemotherapy. Stat1 (Signal Transducer and Activator of Transcription 1) is a member of the Stat family of proteins, which are mediators of Jak signaling. Stat1 is phosphorylated at the tyrosine 701 position by Jak kinases and translocates to the nucleus to activate the transcription of hundreds of Interferon-Stimulated Genes (ISGs).
Further, clinical trials of Jak/Stat pathway inhibitors in hematological malignancies are ongoing for the pharmacological suppression of the Stat-related pathways. Jak inhibitors currently available include either specific inhibitors of Jak2 or combined inhibitors of Jak1 and Jak2. The radiosensitizing effects of the Jak2 inhibitor TG101209 (TargeGen Inc., CAS 936091-14-4) were recently described in two lung cancer cell lines and were associated with suppression of the Stat3 pathway. TG101209 was developed to potentially inhibit myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Activation of Jak2/Stat3 signaling was demonstrated in several other lung cancer cell lines and was associated with increased oncogenic potential, tumor angiogenesis, and EGFR signaling associated with progression of lung adenocarcinomas. Further, next-generation sequencing recently revealed constitutively active Jak2 mutation (V617F) in some lung cancer patients.
To date, few publications describe the application of these drugs in lung cancer models, and mechanisms of their action in lung cancer are still poorly understood. The majority of publications regarding the application of Jak inhibitors in solid tumors, including lung cancer, explain their action based on pathways activated by Stat3, Stat5 or not directly related to Stat signaling. Jak/Stat1 pathways in solid tumors are not described in the context of therapeutic effects of Jak inhibitors, though they are already described in some myelodysplastic diseases. It is believed that Jak1 kinase is activated by Jak2 kinase and both are necessary for activation of Stat1 and Stat3. It is also believed that Stat1 and Stat3 can form heterodimers with transcriptional activity. Additionally, genes induced by Jak2/Stat3 activation overlap with IFN/Stat1-dependent genes. Finally, constitutively active oncogenic Jak2 (Jak2V617F) induces genes overlapping with the Stat1-dependent genes.
While the importance of Jak/Stat signaling, in general, for cancers continues to be investigated, the role that downstream effector genes may play in tumors remains undefined. Consequently, there is an urgent and definite need to identify the downstream effector genes that may potentially have a role in tumor development associated with activation of the Jak/Stat pathway. Such genes may provide new targets for Jak-related therapy of cancers, including, for example, lung cancer, or for sensitization of cancers for chemotherapies and/or radiotherapies. Therefore, there is a need to determine the identities of downstream effector genes in the Jak/Stat pathway of cancer, including solid tumors, that may play a role in treating cancers, and to develop effective cancer therapies around these downstream effector genes. More effective and targeted cancer therapies with potentially fewer side effects are also needed.